WO1991019484A1 - Injectable pharmaceutical composition - Google Patents
Injectable pharmaceutical composition Download PDFInfo
- Publication number
- WO1991019484A1 WO1991019484A1 PCT/EP1991/001096 EP9101096W WO9119484A1 WO 1991019484 A1 WO1991019484 A1 WO 1991019484A1 EP 9101096 W EP9101096 W EP 9101096W WO 9119484 A1 WO9119484 A1 WO 9119484A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- microspheres
- injection
- microsphere
- active substance
- progesterone
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a process for improving the control of the pharmacokinetic and pharmacological properties of pharmaceutically active substances. It also relates to particles of active substances, and their use in injectable formulations with delayed release.
- compositions of the prior art generally have several defects:
- Patent FR 2 070 153 (DUPONT DE NEMOURS) describes suspensions of particles of active principles coated with matrices of polylactide polymers. This technique reduces the initial drug shock effect and slows down the release of the active substance. However, the irregularities in shape again create a risk of an operating incident at the time of injection, and variations in shape, size and internal composition of these particles cause undesirable variability in dissolution rates. in the recipient organism, that is to say a dispersion of the results not allowing an accurate pharmacokinetic prediction.
- EP patent N ° 257,368 (AMERICAN CYANAMID CO) describes a composition for parenteral use consisting of micro ⁇ spheres of fats and / or waxes, of natural or synthetic origin, with low melting point (40-60 ° ), charged with particles of a polypeptide, for example a growth hormone.
- a polypeptide for example a growth hormone.
- these compositions are injected into cattle, the growth hormone sees its dissolution delayed by the coating of wax or fat, which leads to a prolongation of its presence in the animal organism, resulting in an increase in growth or lactation.
- These micro ⁇ spheres tend to deform, clump or coalesce when the ambient temperature is high, especially in tropical countries (40-60 ° C), which can lead to handling or storage problems.
- the proportion of active polypeptide, in the particle is limited in practice to 30 - 40%, the injection of these particles also has the disadvantage of introducing into the body a quantity of foreign carrier substance which is useless to this organism, less than 1.5 - 3 times that of the active substance.
- microcapsules thus formed often contain "central" particles of very different size, or even no central particle at all.
- micro-spheres or micro-capsules of the prior art allows a slowed dissolution, therefore a generally delayed release of the active ingredients, however, taking into account the heterogeneity of shape and mass of the central particles or dispersed ultra fine particles which can be coated in capsules of similar external dimension, the speed of release of the active principle is not homogeneous and a fine control of the release, or even a finely programmed release as a function of time is not possible.
- the object of the present invention is to provide delayed release formulations for administration by parenteral injection, intended for example for the applications mentioned in the preceding paragraph, which allow fine control of this release without having the drawbacks of suspensions of particles or microcapsules of the prior art.
- the speed of dissolution of a microsphere in a given solvent medium is essentially a function of the radius of the sphere, taking into account the relationships between volume, surface and radius of a sphere. .
- the fact of using solid, non-porous spheres makes it possible to have a precise knowledge of the mass-surface relationship of the particles and therefore, thanks to a selection of the caliber of the spheres, that is to say of the radius or of a distribution of rays, to have precise control of the rate of release of the active ingredient (s) administered.
- This same control precision by avoiding overdoses or the need to compensate for underdoses, makes it possible to reduce the total administration of the biologically active substance (s) to the minimum amount required to obtain the desired therapeutic effect. and thus reduce the risk of producing undesirable side effects in the patient.
- the mi ⁇ crospheres according to the present invention have the advantage over the coated or micro-encapsulated particles of the prior art of reducing the volume of solid material to be injected into an organ living nism. They also have the advantage of not introducing unnecessary solid excipient more or less degradable in the body.
- the association can include various pharmaceutically acceptable additive means for improving the stability or the chemical integrity of the biologically active substances, it being understood that 'these are not vector type excci ⁇ pients.
- it may prove useful to lower the melting point or to inhibit a decomposition reaction during the process of fa ⁇ brication (for example the process by fusion-freezing) of the microspheres.
- the microspheres according to the present invention have the advantage of having less tendency to clump together and to pass more fluidly. by a hypodermic needle.
- microspheres can be sorted and separated in a finer and more reliable manner according to their size, than particles of irregular shapes.
- the formulation according to the present invention may be in the form of microsphere powder in flasks-ampoules, ready to be suspended, or in the form of a suspension already prepared in injec ⁇ ampules ready to be administered in human or veterinary medicine .
- the suspension medium can be water, saline solution, oil, containing buffers, surfactants, preservatives, usually used in suspensions injectable by pharmaco-technicians, or any other substance or combination which does not does not threaten the physical and chemical integrity of the suspended substances and which is suitable for the organism which will receive it.
- the diameter of the injection syringe needles is good to limit the diameter of the microspheres to 300 microns and more preferably to 100 microns.
- the diameter of the microsphere can be reduced to 1 micron.
- microspheres whose diameter is comprised between 5 and 100 microns, depending on the active substances.
- An essential condition for producing the dosage form according to the present invention is to have batches of calibrated microspheres, that is to say homogeneous in diameter. If necessary, sorting of the microspheres according to their diameter can be carried out during manufacture using known methods: for example by cyclonic separators, by sieving with air suction or by sieving in the medium liquid. In practice, it is sufficient that more than 70% of the microspheres have diameters between 70% and 130% of a specified diameter. If necessary, the ideal dissolution curve, determined by the envisaged application, can be approached by carrying out a mixture of batches having appropriate different diameters. Methods for putting a solid product in the form of microspheres, by mechanical abrasion, are known in the state of the art.
- Patent WO 90/13285 describes a process for the manufacture of porous microspheres obtained by spraying, freezing and lyophilization in a cold gas, of substances previously dissolved in an adequate solvent.
- the formulations according to the present invention are particularly suitable for substances whose melting temperature is above 60 ° and which are thermostable above their fu ⁇ sion (or which can be made thermostable using additives) to be able to undergo the manufacturing process.
- An additive can also be used to suppress a phase transition, from a solid phase to another solid phase, capable of weakening the structure of the sphere.
- the process is also suitable for mixtures of active substances in solid solution, one inside the other.
- Figure 1 shows the manufacturing scheme of micro ⁇ spheres according to the present invention.
- FIG. 5 represents an experimental setup for determining the rate of dissolution of microspheres.
- Figure 6 shows the compared dissolution profiles of microspheres and progesterone crystals (50-125 ⁇ m).
- FIG. 7 shows the comparative dissolution rates of microspheres and progesterone crystals in the form of derivatives of optical absorbance as a function of time.
- Figures 8 and 9 show the compared dissolution profiles of microspheres and crystals of 17- ⁇ - estradiol (50 to 100 ⁇ m).
- Figures 10 and 11 show the comparative dissolu ⁇ tion profiles of microspheres and proges ⁇ terone crystals (50 to 100 ⁇ m).
- Figures 12 and 13 show the compared dissolu ⁇ tion profiles of microspheres and naproxene crystals.
- Figures 14, 15, 16 show the plasma levels obtained (in rabbits) with progesterone by injection, respectively of an oily solution, of crystals of average size 44 ⁇ m, and of microspheres of average size 44 ⁇ m.
- FIGS 17, 18, 19 show the plasma levels obtained (in rabbits) with 17- ⁇ -estradiol by injection, respectively of an oily solution, of crystals and of microspheres.
- FIG. 20 shows the plasma levels obtained (in rabbits) with naproxen, respectively of a solution (curve 0), of crystals (curve 1) and of microspheres (curve 2).
- Figures 21 and 22 show the comparative dissolu ⁇ tion profiles of microspheres and indomethacin crystals (50 to 100 ⁇ m).
- Preheated nitrogen under pressure is sent through the inlet tube A x into the spray device and passes through a thermo-regulated heating zone B where it is brought to a temperature between 125 and 130 ° C, before being admitted into the sprayer D.
- a tank E contains liquid nitrogen which evaporates and enters several pipes in the form of ultra cold gas, at high speed, into the spray-freezing chamber F, where it meets the progesterone mist.
- the droplets, immediately after their formation by the sprayer are surrounded by a stream of glacial gas which crystallizes them into microspheres and prevents them from touching the walls before their total solidification.
- the temperature at the outlet of the spray-freezing chamber is between - 15 ° and - 50 ° C. All of the microspheres produced using this chamber F have a perfect spherical shape.
- At the exit from chamber F are two cyclonic separators, G_, G 2 , (of construction known elsewhere) connected in series.
- Figure 3 shows a photomicrograph of a fraction of these microspheres, with an average diameter of 100 ⁇ m.
- Example 3 Particle size distribution.
- Cholesterol microspheres are produced by the same operating process as in Example 1. After separation, the fraction with an average diameter of 25 ⁇ m has the particle size distribution shown in FIG. 4.
- Example 4 Manufacture of naproxen microspheres.
- Example 1 The method of Example 1 is used. Operating conditions:
- Example 1 The method of Example 1 is used. Operating conditions:
- Example 1 The method of Example 1 is used. Operating conditions:
- Example 1 The method of Example 1 is used. Operating conditions:
- Thermography should also be used, not only to clearly define the melting points, but also to determine whether there are endothermic or exothermic forms which may just as well express structural modifications or polymorphism, susceptible of 'have an effect on the process of formation of microspheres, that chemical degradation produced by heating.
- Device used in ultraviolet spectrography Hewlett Packard model 8452A with arrangement of photo diodes, with quartz cell having a beam of 0.1 cm.
- Solvents ethanol for 17- ⁇ -estradiol, proges ⁇ terone and cholesterol; 0.1 N HC1 for naproxene, 0.1 NaOH for indomethacin.
- Chromatograph high resolution liquid with detection by arrangement of photodiodes: Waters 990 and N.E.C. Powermate 2 workstation.
- Thermograph SHIMADZU DSC-50 Calormeter and CR4A work ⁇ station.
- thermograms show that there has been no chemical alteration of the substances (example: TF crystals: 130 ° C, TF microspheres: 129 ° C for progesterone).
- the thermograms of progesterone and 17- ⁇ -estradiol show only a morphological modification of the solid crystal phases.
- Example 8 Dissolution curves of progesterone microspheres.
- the tests can be carried out either in pure water or in a water / polypropylene glycol 1: 1 medium to accelerate the dissolution.
- the experimental setup is shown in FIG. 5.
- An infusion cell 1, containing the sample, is supplied by a (stirred) reservoir of dissolution medium 2; both are contained in a bain-marie 3.
- the optical density of the medium, at 240 nm, is recorded by a spectrophotometer 4 and the medium is brought back into the tank.
- a bubble trap 5 and a peristaltic pump 6 complete the circuit.
- Figure 6 shows the compared dissolution profiles of microspheres (curve 2) and crystals (curve 1) of granulo etries between 50 and 125 ⁇ m, measured by the variation of optical absorbance as a function of time. The test is carried out in a water / PPG 50:50 medium. It is found that the dissolution is delayed by the forming of microspheres.
- FIG. 7 shows the dissolution rates (derived from variations in DO as a function of time) of crystals (1) and microspheres (2) of the same average particle size (approximately 150 ⁇ m).
- the granulometric distribution of the crystals is more heterogeneous and their dissolution curve more irregular than that of the microspheres.
- the following examples show the comparative reproducibility of the initial parts of the curves for dissolving crystals and microspheres of comparable particle size, of the same product.
- the apparatus used is that of FIG. 5.
- Several (3 - 6) measurement circuits (dissolving cells and tubes) containing identical samples, are implemented in parallel by the same peristaltic pump and measured if simultaneously.
- Example 10 Dissolution of progesterone crystals (fig. 11) / progesterone microspheres (fig. 10).
- Dissolution medium used H 2 0 HPLC quality with
- Spectrophotometry wavelength 240 nm
- Example 11 Dissolution of microspheres of naproxene (fig. 12) / crystals of naproxene (fig. 13).
- the apparatus used is that of figure N ° 5.
- Dissolution medium used H 2 0 HPLC quality with
- Example 12 Dissolution of microspheres of 17- ⁇ -estradiol: (Fig. 9) / crystals of 17- ⁇ -estradiol (fig. 8). The apparatus used is that of figure N ° 5.
- Dissolution medium used H 2 0 HPLC quality with
- the set of curves shows that the reproducibility of the results and the regularity of the dissolution profiles is better for batches of microspheres than for batches of crystals, in the initial phase of dissolution (which is the most critical period).
- Example 15 Study of the plasma levels of progesterone in rabbits (fig. 14, 15, 16).
- the study includes the comparative evaluation of the effect on plasma levels in rabbits produced by parenteral administration of progesterone in the form of an oily solution (0), an aqueous suspension of crystals (1) and of an aqueous suspension of microspheres (2) (formula No. 1, average particle size: 44 ⁇ m)
- the intakes are 2 ml per venipuncture, are centrifuged, then kept at -20 ° C until analysis by radioimmunoanalysis.
- Example 16 Study of plasma estradiol levels in rabbits.
- the study includes the comparative evaluation of the effect on plasma levels in rabbits, produced by parenteral administration of estradiol in the form of an oily solution (0), an aqueous suspension of crystals (1) and an aqueous suspension of estradiol microspheres (2) (formula No. 2, particle size 50-100 ⁇ m).
- the sampling interval is 1, 2, 4 and 24 hours for 20 days, then every three days until reaching 30 days.
- Example 17 Comparative evolution of plasma levels of naproxen in oily solution and in suspension of microspheres.
- the reference point is 5 ml of blood per cardiac puncture, followed by the intramuscular administration of 2 ml of the formula to be tested (formula 3) in the lower right member.
- the catches to be analyzed were taken at 30 min intervals. for 2 hours and at 60 min intervals. up to 6 hours. In several trials, depending on the kinetic characteristics of the drug, there were additional intakes.
- test samples also taken by cardiac puncture, were placed in Vacutainer, added with heparin, centrifuged at 3000 rpm for 10 min. , then the plasma separated and frozen in cryotubes at -20 ° C until its analysis.
- FIG. 20 shows that the variation in plasma levels, reached after injection of microspheres, is much more regular than that obtained after injection of particles of any shape (50-100 ⁇ m).
- the manufacturing process described above, the spherical structures and the formulations obtained and their use by parenteral injection are not of course limited to the substances given in the examples above, but are applicable to all pharmacologically sub ⁇ stances. active, chemically stable during icronization, provided that the pharmacokinetic changes that the microspheres allow (short or long duration depending on the diameter, regularization of plasma profiles), have a therapeutic or convenience advantage and that the doses to be administered do not exceed a reasonable volume.
- the mode of administration can be chosen from hypodermic injection, subcutaneous injection, intramuscular injection, intra-articular injection and intra-spinal injection, depending on the intended application. .
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Abstract
Description
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE69103419T DE69103419T2 (en) | 1990-06-14 | 1991-06-12 | INJECTABLE MEDICINAL PRODUCT. |
BR919106545A BR9106545A (en) | 1990-06-14 | 1991-06-12 | PROCESS OF PHARMACY-TECHNICAL TREATMENT OF A PHARMACEUTICALLY ACTIVE, INJECTABLE SUBSTANCE |
UA93004686A UA27043C2 (en) | 1990-06-14 | 1991-06-12 | Microspherical particles for the parenteral injection of pharmaceutically active agent in its control releasing in organism after injection, method for its producing and suspension based on these microspheres |
EP91910762A EP0533739B1 (en) | 1990-06-14 | 1991-06-12 | Injectable pharmaceutical composition |
AU80847/91A AU661275B2 (en) | 1990-06-14 | 1991-06-12 | Injectable pharmaceutical composition |
RU92016471A RU2104692C1 (en) | 1990-06-14 | 1991-06-12 | Solid nonporous microsphere, method of its producing and suspension for parenteral injection based on these microspheres |
FI925661A FI107698B (en) | 1990-06-14 | 1992-12-11 | Solid, non-porous microspheres |
NO924792A NO302998B1 (en) | 1990-06-14 | 1992-12-11 | Microspheres, method of preparation and use thereof in the preparation of a preparation |
BG97166A BG61179B1 (en) | 1990-06-14 | 1992-12-14 | Medicamentoud parenteral form with depot effect |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR90/07416 | 1990-06-14 | ||
FR9007416A FR2663223B1 (en) | 1990-06-14 | 1990-06-14 | PARENTERAL GALENIC FORM. |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1991019484A1 true WO1991019484A1 (en) | 1991-12-26 |
Family
ID=9397598
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1991/001096 WO1991019484A1 (en) | 1990-06-14 | 1991-06-12 | Injectable pharmaceutical composition |
Country Status (30)
Country | Link |
---|---|
US (3) | US5360616A (en) |
EP (1) | EP0533739B1 (en) |
JP (1) | JP2675675B2 (en) |
KR (1) | KR0157439B1 (en) |
CN (1) | CN1057442C (en) |
AT (1) | ATE109658T1 (en) |
AU (1) | AU661275B2 (en) |
BG (1) | BG61179B1 (en) |
BR (1) | BR9106545A (en) |
CA (1) | CA2085344C (en) |
CZ (1) | CZ286793B6 (en) |
DE (1) | DE69103419T2 (en) |
DK (1) | DK0533739T3 (en) |
ES (1) | ES2059142T3 (en) |
FI (1) | FI107698B (en) |
FR (1) | FR2663223B1 (en) |
HU (1) | HUT68709A (en) |
IE (1) | IE62679B1 (en) |
IL (1) | IL98459A (en) |
NO (1) | NO302998B1 (en) |
NZ (1) | NZ238542A (en) |
PL (1) | PL167234B1 (en) |
PT (1) | PT97975B (en) |
RU (1) | RU2104692C1 (en) |
SK (1) | SK280564B6 (en) |
TN (1) | TNSN91048A1 (en) |
UA (1) | UA27043C2 (en) |
UY (1) | UY23240A1 (en) |
WO (1) | WO1991019484A1 (en) |
ZA (1) | ZA914550B (en) |
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FR2732621A1 (en) * | 1995-04-10 | 1996-10-11 | Rhone Poulenc Chimie | PEARLS OF A PRODUCT HAVING THE SURFUSION PHENOMENON AND PROCESS FOR OBTAINING THE SAME |
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WO2009128692A1 (en) * | 2008-04-14 | 2009-10-22 | Posi Visionary Solutions Llp | Method and pharmaceutical composition for obtaining the plasmatic progesterone levels required for different therapeutic indications |
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FR2663224B1 (en) * | 1990-06-14 | 1995-01-20 | Applicationes Farmaceuticas Sa | PARENTERAL GALENIC FORM. |
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- 1991-06-12 KR KR1019920703205A patent/KR0157439B1/en not_active IP Right Cessation
- 1991-06-12 HU HU9203958A patent/HUT68709A/en unknown
- 1991-06-12 DK DK91910762.3T patent/DK0533739T3/en active
- 1991-06-12 ES ES91910762T patent/ES2059142T3/en not_active Expired - Lifetime
- 1991-06-12 BR BR919106545A patent/BR9106545A/en not_active Application Discontinuation
- 1991-06-12 EP EP91910762A patent/EP0533739B1/en not_active Expired - Lifetime
- 1991-06-12 UA UA93004686A patent/UA27043C2/en unknown
- 1991-06-12 AT AT91910762T patent/ATE109658T1/en not_active IP Right Cessation
- 1991-06-12 AU AU80847/91A patent/AU661275B2/en not_active Ceased
- 1991-06-12 CA CA002085344A patent/CA2085344C/en not_active Expired - Fee Related
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- 1991-06-12 JP JP3510331A patent/JP2675675B2/en not_active Expired - Lifetime
- 1991-06-12 DE DE69103419T patent/DE69103419T2/en not_active Expired - Fee Related
- 1991-06-12 RU RU92016471A patent/RU2104692C1/en active
- 1991-06-13 SK SK1816-91A patent/SK280564B6/en unknown
- 1991-06-13 IE IE201791A patent/IE62679B1/en not_active IP Right Cessation
- 1991-06-13 CZ CS19911816A patent/CZ286793B6/en not_active IP Right Cessation
- 1991-06-13 UY UY23240A patent/UY23240A1/en not_active IP Right Cessation
- 1991-06-13 US US07/714,583 patent/US5360616A/en not_active Expired - Lifetime
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- 1991-06-14 CN CN91104859A patent/CN1057442C/en not_active Expired - Fee Related
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1992
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Cited By (18)
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FR2732621A1 (en) * | 1995-04-10 | 1996-10-11 | Rhone Poulenc Chimie | PEARLS OF A PRODUCT HAVING THE SURFUSION PHENOMENON AND PROCESS FOR OBTAINING THE SAME |
EP0737509A1 (en) * | 1995-04-10 | 1996-10-16 | Rhone-Poulenc Chimie | Crystallized beads of a product which can be supercooled and process to prepare them |
US5766521A (en) * | 1995-04-10 | 1998-06-16 | Rhone-Poulenc Chimie | Process for obtaining cristallized pearls exhibiting the phenomenon of supercooling |
US6663895B2 (en) | 1998-02-25 | 2003-12-16 | John-Claude Savoir | Stable shaped particles of crystalline organic compounds |
US7427413B2 (en) | 1998-02-25 | 2008-09-23 | Skendi Finance Ltd. | Stable shaped particles of crystalline organic compounds |
US6528094B1 (en) | 1998-02-25 | 2003-03-04 | John-Claude Savoir | Stable shaped particles of crystalline organic compounds |
US6537580B1 (en) | 1998-02-25 | 2003-03-25 | John-Claude Savoir | Stable shaped particles of crystalline organic compounds |
US6638536B2 (en) | 1998-02-25 | 2003-10-28 | John-Claude Savoir | Stable shaped particles of crystalline organic compounds |
WO1999043304A1 (en) * | 1998-02-25 | 1999-09-02 | John Claude Savoir | Stable shaped particles of crystalline organic compounds |
US6737081B2 (en) | 1998-02-25 | 2004-05-18 | John-Claude Savoir | Stable shaped particles of crystalline organic compounds |
US6287693B1 (en) | 1998-02-25 | 2001-09-11 | John Claude Savoir | Stable shaped particles of crystalline organic compounds |
EP2085075A1 (en) * | 1998-02-25 | 2009-08-05 | Skendi Finance, Ltd. | Stable shaped particles of crystalline organic compounds |
EP2319497A1 (en) * | 1998-02-25 | 2011-05-11 | Skendi Finance, Ltd. | Stable shaped particles of crystalline organic compounds |
US7589082B2 (en) | 2003-06-13 | 2009-09-15 | Skendi Finance Ltd | Pharmaceutical formulation for contraception and hormone-replacement therapy |
US8163722B2 (en) | 2003-06-13 | 2012-04-24 | Skendi Finance Ltd. | Pharmaceutical formulation for contraception and hormone-replacement therapy |
WO2009128692A1 (en) * | 2008-04-14 | 2009-10-22 | Posi Visionary Solutions Llp | Method and pharmaceutical composition for obtaining the plasmatic progesterone levels required for different therapeutic indications |
US10898432B2 (en) | 2015-12-18 | 2021-01-26 | Proinvet Innovations S.A. | Formulations and methods for controlling the reproductive cycle and ovulation |
CN106063783A (en) * | 2016-06-16 | 2016-11-02 | 浙江爱生药业有限公司 | A kind of Progesterone slow-releasing microcapsule preparation and preparation method thereof |
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